This is an application for a K08 Mentored Clinical Scientist Development Award from a clinically trained rheumatologist who now seeks to expand his career to become an independent physician scientist. Epstein- Barr virus (EBV) infection is more common in patients with systemic lupus erythematosus (SLE) than control subjects, suggesting that this virus plays an etiologic role in disease and/or that patients with lupus have impaired EBV-specific immune responses. The results of preliminary study of this proposal has demonstrated that patients with SLE have a defect in controlling latent EBV infection as evidenced by the increased EBV viral loads and altered EBV-specific T cell responses compared to healthy controls. Of interest, studies reported an increased frequency of herpes zoster due to reactivation of varicella zoster virus (VZV) in patients with SLE and increased EBV viral loads in peripheral blood of patients with rheumatoid arthritis (RA). These findings raise several questions: 1) whether the defect in controlling latent EBV infection is a unique finding in SLE or a global phenomenon in chronic immune-mediated diseases such as RA; and 2) whether this defect in SLE is limited to EBV or relavent to other latent viral infections such as VZV and cytomegalovirus (CMV). Next issues are the mechanisms for this defect and its clinical significance. To address these questions, three specific aims are planned. First, numerical and functional differences in EBV- and VZV-specific T cells between patients with SLE and healthy and diseased (RA) controls will be sought. Here, EBV- and VZV-specific CD4+ and CD8+ T cells in peripheral blood will be analyzed using MHC class I tetramers, flow cytometry following short-term in vitro stimulation and cytotoxic assay. EBV viral loads in peripherla blood will be measured using real-time PCR. Second, to find if the defect is secondary to immunosuppressive drugs and/or immune activation, EBV- and VZV- specific T cell responses and EBV viral loads in patients with new onset SLE will be determined using the same assays. Third, the effects of immunosuppressive therapies on EBV- and VZV-specific T cells and EBV viral loads in SLE will be assessed by serially measuring the frequency and function of EBV- and VZV-specific T cells and EBV viral loads before and after immunosuppressive therapies.